Ischemic heart disease, or coronary heart disease, kills more Americans per year than any other single cause. In 2004, one in every five deaths in the United States resulted from ischemic heart disease. Indeed, the disease has had a profound impact worldwide. If left untreated, ischemic heart disease can lead to chronic heart failure, which can be defined as a significant decrease in the heart's ability to pump blood. Chronic heart failure is often treated with drug therapy.
Ischemic heart disease is generally characterized by a diminished flow of blood to the myocardium and is also often treated using drug therapy. Although many of the available drugs may be administered systemically, local drug delivery (“LDD”) directly to the heart can result in higher local drug concentrations with fewer systemic side effects, thereby leading to improved therapeutic outcomes.
Cardiac drugs may be delivered locally via catheter passing through the blood vessels to the inside of the heart. However, endoluminal drug delivery has several shortcomings, such as: (1) inconsistent delivery, (2) low efficiency of localization, and (3) relatively rapid washout into the circulation.
To overcome such shortcomings, drugs may be delivered directly into the pericardial space, which surrounds the external surface of the heart. The pericardial space is a cavity formed between the heart and the relatively stiff pericardial sac that encases the heart. Although the pericardial space is usually quite small because the pericardial sac and the heart are in such close contact, a catheter may be used to inject a drug into the pericardial space for local administration to the myocardial and coronary tissues. Drug delivery methods that supply the agent to the heart via the pericardial space offer several advantages over endoluminal delivery, including: (1) enhanced consistency and (2) prolonged exposure of the drug to the cardiac tissue.
In current practice, drugs are delivered into the pericardial space either by the percutaneous transventricular method or by the transthoracic approach. The percutaneous transventricular method involves the controlled penetration of a catheter through the ventricular myocardium to the pericardial space. The transthoracic approach involves accessing the pericardial space from outside the heart using a sheathed needle with a suction tip to grasp the pericardium, pulling it away from the myocardium to enlarge the pericardial space, and injecting the drug into the space with the needle.
For some patients with chronic heart failure, cardiac resynchronization therapy (“CRT”) can be used in addition to drug therapy to improve heart function. Such patients generally have an abnormality in conduction that causes the right and left ventricles to beat (i.e., begin systole) at slightly different times, which further decreases the heart's already-limited function. CRT helps to correct this problem of dyssynchrony by resynchronizing the ventricles, thereby leading to improved heart function. The therapy involves the use of an implantable device that helps control the pacing of at least one of the ventricles through the placement of electrical leads onto specified areas of the heart. Small electrical signals are then delivered to the heart through the leads, causing the right and left ventricles to beat simultaneously.
Like the local delivery of drugs to the heart, the placement of CRT leads on the heart can be challenging, particularly when the target placement site is the left ventricle. Leads can be placed using a transvenous approach through the coronary sinus, by surgical placement at the epicardium, or by using an endocardial approach. Problems with these methods of lead placement can include placement at an improper location (including inadvertent placement at or near scar tissue, which does not respond to the electrical signals), dissection or perforation of the coronary sinus or cardiac vein during placement, extended fluoroscopic exposure (and the associated radiation risks) during placement, dislodgement of the lead after placement, and long and unpredictable times required for placement (ranging from about 30 minutes to several hours).
Clinically, the only approved non-surgical means for accessing the pericardial space include the subxiphoid and the ultrasound-guided apical and parasternal needle catheter techniques, and each methods involves a transthoracic approach. In the subxiphoid method, a sheathed needle with a suction tip is advanced from a subxiphoid position into the mediastinum under fluoroscopic guidance. The catheter is positioned onto the anterior outer surface of the pericardial sac, and the suction tip is used to grasp the pericardium and pull it away from the heart tissue, thereby creating additional clearance between the pericardial sac and the heart. The additional clearance tends to decrease the likelihood that the myocardium will be inadvertently punctured when the pericardial sac is pierced.
Although this technique works well in the normal heart, there are major limitations in diseased or dilated hearts—the very hearts for which drug delivery and CRT lead placement are most needed. When the heart is enlarged, the pericardial space is significantly smaller and the risk of puncturing the right ventricle or other cardiac structures is increased. Additionally, because the pericardium is a very stiff membrane, the suction on the pericardium provides little deformation of the pericardium and, therefore, very little clearance of the pericardium from the heart.
As referenced above, the heart is surrounded by a “sac” referred to as the pericardium. The space between the surface of the heart and the pericardium can normally only accommodate a small amount of fluid before the development of cardiac tamponade, defined as an emergency condition in which fluid accumulates in the pericardium. Therefore, it is not surprising that cardiac perforation can quickly result in tamponade, which can be lethal. With a gradually accumulating effusion, however, as is often the case in a number of diseases, very large effusions can be accommodated without tamponade. The key factor is that once the total intrapericardial volume has caused the pericardium to reach the noncompliant region of its pressure-volume relation, tamponade rapidly develops. Little W. C., Freeman G. L. (2006). “Pericardial Disease.” Circulation 113(12): 1622-1632.
Cardiac tamponade occurs when fluid accumulation in the intrapericardial space is sufficient to raise the pressure surrounding the heart to the point where cardiac filling is affected. Ultimately, compression of the heart by a pressurized pericardial effusion results in markedly elevated venous pressures and impaired cardiac output producing shock which, if untreated, it can be rapidly fatal. Id.
The frequency of the different causes of pericardial effusion varies depending in part upon geography and the patient population. Corey G. R. (2007). “Diagnosis and treatment of pericardial effusion.” http://patients.uptodate.com. A higher incidence of pericardial effusion is associated with certain diseases. For example, twenty-one percent of cancer patients have metastases to the pericardium. The most common are lung (37% of malignant effusions), breast (22%), and leukemia/lymphoma (17%). Patients with HIV, with or without AIDS, are found to have increased prevalence, with 41-87% having asymptomatic effusion and 13% having moderate-to-severe effusion. Strimel W. J. e.a. (2006). “Pericardial Effusion.” http://www.emedicine.com/med/topic1786.htm.
End-stage renal disease is a major public health problem. In the United States, more than 350,000 patients are being treated with either hemodialysis or continuous ambulatory peritoneal dialysis. Venkat A., Kaufmann K. R., Venkat K. (2006). “Care of the end-stage renal disease patient on dialysis in the ED.” Am J Emerg Med 24(7): 847-58. Renal failure is a common cause of pericardial disease, producing large pericardial effusions in up to 20% of patients. Task Force members, Maisch B., Seferovic P. M., Ristic A. D., Erbel R., Rienmuller R., Adler Y., Tomkowski W. Z., Thiene G., Yacoub M. H., ESC Committee for Practice Guidelines, Priori S. G., Alonso Garcia M. A., Blanc J. J., Budaj A., Cowie M., Dean V., Deckers J., Fernandez Burgos E., Lekakis J., Lindahl B., Mazzotta G., Morales J., Oto A., Smiseth O. A., Document Reviewers, Acar J., Arbustini E., Becker A. E., Chiaranda G., Hasin Y., Jenni R., Klein W., Lang I., Luscher T. F., Pinto F. J., Shabetai Simoons M. L., Soler Soler J., Spodick D. H. (2004). “Guidelines on the Diagnosis and Management of Pericardial Diseases Executive Summary: The Task Force on the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology.” Eur Heart J 25(7): 587-610.
Viral pericarditis is the most common infection of the pericardium. Inflammatory abnormalities are due to direct viral attack, the immune response (antiviral or anticardiac), or both. Id. Purulent (bacterial) pericarditis in adults is rare, but always fatal if untreated. Mortality rate in treated patients is 40%, mostly due to cardiac tamponade, toxicity, and constriction. It is usually a complication of an infection originating elsewhere in the body, arising by contiguous spread or haematogenous dissemination. Id. Other forms of pericarditis include tuberculous and neoplastic.
The most common secondary malignant tumors are lung cancer, breast cancer, malignant melanoma, lymphomas, and leukemias. Effusions may be small or large with an imminent tamponade. In almost two-thirds of the patients with documented malignancy pericardial effusion is caused by non-malignant diseases, e.g., radiation pericarditis, or opportunistic infections. The analyses of pericardial fluid, pericardial or epicardial biopsy are essential for the confirmation of malignant pericardial disease. Id.
Management of pericardial effusions continues to be a challenge. There is no uniform consensus regarding the best way to treat this difficult clinical entity. Approximately half the patients with pericardial effusions present with symptoms of cardiac tamponade. In these cases, symptoms are relieved by pericardial decompression, irrespective of the underlying cause. Georghiou G. P., Stamler A., Sharoni E., Fichman-Horn S., Berman M., Vidne B. A., Saute M. (2005). “Video-Assisted Thoracoscopic Pericardial Window for Diagnosis and Management of Pericardial Effusions.” Ann Thorac Surg 80(2): 607-610. Symptomatic pericardiac effusions are common and may result from a variety of causes. When medical treatment has failed to control the effusion or a diagnosis is needed, surgical intervention is required. Id.
The most effective management of pericardial effusions has yet to be identified. The conventional procedure is a surgically placed pericardial window under general anesthesia. This procedure portends significant operative and anesthetic risks because these patients often have multiple comorbidities. Less invasive techniques such as blind needle pericardiocentesis have high complication and recurrence rates. The technique of echocardiographic-guided pericardiocentesis with extended catheter drainage is performed under local anesthetic with intravenous sedation. Creating a pericardiostomy with a catheter in place allows for extended drainage and sclerotherapy. Echocardiographic-guided pericardiocentesis has been shown to be a safe and successful procedure when performed at university-affiliated or academic institutions. However, practices in community hospitals have rarely been studied in detail. Buchanan C. L., Sullivan V. V., Lampman R., Kulkarni M. G. (2003). “Pericardiocentesis with extended catheter drainage: an effective therapy.” Ann Thorac Surg 76(3): 817-82.
The treatment of cardiac tamponade is drainage of the pericardial effusion. Medical management is usually ineffective and should be used only while arrangements are made for pericardial drainage. Fluid resuscitation may be of transient benefit if the patient is volume depleted (hypovolemic cardiac tamponade).
Surgical drainage (or pericardiectomy) is excessive for many patients. The best option is pericardiocentesis with the Seldinger technique, leaving a pigtail drainage catheter that should be kept in place until drainage is complete. Sagrista Sauleda J., Permanyer Miralda G., Soler Soler J. (2005). “[Diagnosis and management of acute pericardial syndromes].” Rev Esp Cardiol 58(7): 830-41. This less-invasive technique resulted in a short operative time and decreased supply, surgeon, and anesthetic costs. When comparing procedure costs of a pericardial window versus an echo-guided pericardiocentesis with catheter drainage at our institution, there was a cost savings of approximately $1,800/case in favor of catheter drainage. In an era of accelerating medical costs, these savings are of considerable importance. Buchanan C. L., Sullivan V. V., Lampman R., Kulkarni M. G. (2003). “Pericardiocentesis with extended catheter drainage: an effective therapy.” Ann Thorac Surg 76(3): 817-82.
Myocardial infarctions (heart attacks) affect a significant number of people, typically resulting in damaged heart tissue from a lack of blood flow. The area surrounding the myocardial infarct, known as the border zone, is the border between the non-viable tissue from the myocardial infarct and its surrounding viable tissue. Over time, as the border zone expands (due to a lack of myocardial infarct healing), the heart will fail, typically resulting in death.
Healthy myocardium is uniformly irrigated, meaning that the tissue receives its needed blood flow in order to remain healthy. If such tissue becomes deprived of blood (from a myocardial infarction), areas of the tissue may become “patchy” or contain “islands” of health tissue and/or damaged tissue.
Attempts to facilitate infarct healing date back to at least 1993, when Fleischmann et al. introduced a therapeutic method for open fractures which combined conventional negative pressure drainage with modern occlusive dressing. The technique later became known as vacuum-assisted closure (VAC) technique, which obtained certification by the U.S. Food and Drug Administration. Chen S. Z. et al. (2005). “Effects of vacuum-assisted closure on wound microcirculation: an experimental study.” Asian J. Surg. 28(3): 2.11-7. The VAC technique applies sub-atmospheric pressure by controlled suction through a porous dressing.
In 1999, Obdeijn and colleagues applied this new method for treatment for posteternotomy mediastinitis. Although scientific evidence for VAC efficacy for promotion of wound healing is established, the effects on heart and lung function are still not fully understood. Petzina R. et al. (2007). “Hemodynamic effects of vacuum-assisted closure therapy in cardiac surgery: assessment using magnetic resonance imaging.” J. Thorac. Cardiovasc. Surg. 133(5): 1154-62.
The major objectives of VAC are to clean the wound, reduce wound edema and infection, improve local blood flow, and promote the growth of healthy granulation tissue. Chen et al. 2005. VAC has been shown to significantly increase blood volume, and the increase in blood flow was related to the increase in capillary caliber, density, and angiogenesis. Id.
Negative pressure is thought to cause an increase in blood flow due to a pressure gradient of blood between the wound and surrounding tissues. This would passively dilate the capillaries and open up the capillary bed of the organ of interest. The VAC treatment has also been shown to restore the integrity of the basement membrane and reduce the endothelial space.
The VAC device produces microdeformations of the wound surface in contact with a foam. An application of the microdeformational wound therapy (MDWT) may cause local wound hypoxia, which is a potent stimulator of vascular endothelial growth factor (VEGF) production. Greene A. K. et al. (2006). “Microdeformational wound therapy: effects on angiogenesis and matrix metalloproteinases in chronic wounds of 3 debilitated patients,” Ann. Plast. Surg. 56(4): 418-22. MDWT increases angiogenesis and reduces metalloproteinase (MMP) activity, both of which promote chronic wound healing. Id.
For the left ventricle, it has been demonstrated that an imbalance between MMP and tissue inhibitor MMPs occurs in the post-myocardial infarct (MI) myocardium, and that increased MMP proteolytic activity facilitates post-MI remodeling and eventually LV dilation. Webb et al., Circulation, September 2006; 114: 1020-1027.
Healing is an interdependent process that involves complex interactions between cells, the cellular microenvironment, biochemical mediators, and extracellular matrix molecules that results in a functional restoration of the injured tissue. The rate of wound healing is restricted by the available vascular supply and the rates of formation of new capillaries and matrix molecules. Morykwas M. J. et al. (1997). “Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation.” Ann. Plast. Surg. 38(6): 553-62. The increase in localized blood flow following application of sub-atmospheric pressure may be due to active removal of the excess interstitial fluid from the tissues surrounding the wound, decompressing small blood vessels and restoring blood flow. Id.
A mechanical stretch of adult cardiac myocytes or neonatal myocytes cultured in serum-free media by 10 to 20 percent above resting length increases protein synthesis without DNA synthesis (hypertrophy). This demonstrates that cardiac myocytes can sense external load in the absence of neuronal and hormonal factors. A stretch of cardiac myocytes in vitro also causes transcriptional activation of immediate-early genes followed by an induction of the fetal genes. VAC may provide the stretch stimulus known to show efficacy.
Previous studies on VAC therapy in pig models have shown that −125 mmHg is the optimal negative pressure for wound healing which has been established as a standard pressure in clinical use. On the heart surface, pressures as low as −25 mmHg have been shown to be effective in increasing microvascular flow.
In continuous sub-atmospheric pressure-treated wound, the granulation tissue showed hyper-proliferative growth above the margins of the wound. In an intermittent sub-atmospheric pressure-treated wound, the mean increase in rate of granulation tissue formation was significantly greater than in control wounds. Morykwas M. J. et al., 1997.
A single mechanical stretch causes an up-regulation of cells whereas intermittent application of sub-atmospheric pressure results in repetitive release of second messengers. This continual stimulation is shown in the more rapid deposition of granulation tissue in wounds exposed to intermittent sub-atmospheric pressure as compared to wounds exposed to continuous sub-atmospheric pressure. Changes in cellular shape increase proliferation and protein and matrix molecule synthesis and promote granulation tissue formation. Id.
Regarding heart reinforcement, left ventricular remodeling after acute myocardial infarction is a complex process that either produces a compensated ventricle with stable hemodynamics or an uncompensated ventricle that progressively enlarges and eventually fails. Bowen F. W. et al. (2001). “Restraining acute infarct expansion decreases collagenase activity in borderzone myocardium.” Ann. Thorac. Surg. 72(6): 1950-6. The changes in the cardiac collagen network occur after myocardial infarct. Reparative fibrosis results in response to a loss of myocardial material after necrosis or apoptosis, due to myocardial ischemia or senescence. Piuhola J. (2002). “Regulation of cardiac responses to increased load: Role of endothelin-I, angiotensin II and collagen XV.”
Materials currently available for cardiac patching include synthetics, such as woven nylon (Dacron) and expanded polytetrafluoroethlyene (ePTFE), as well as glutaraldehyde-cross-linked biological membranes, like bovine pericardium. Although such materials perform adequately to fill tissue voids or reinforce weaknesses, they have no capacity for bioresorption, and therefore do not become viable. Such patches become incorporated by fibrotic encapsulation and cannot restore regional tissue functionality. Robinson K. A. et al. (2005). “Extracellular matrix scaffold thr cardiac repair.” Circulation 112 (9 Suppl): 1135-43.
Polymer scaffolds can be produced from natural or synthetic materials. Natural materials may mimic the native cellular environment as they are often extracellular matrix components, and may include collagen, hydroxyapatite, Matrigel, alginate, etc. Synthetic materials have the advantage of having selected material properties such as strength, degradation time, porosity, and microstructure.
Growth factors can also be incorporated into the matrix, wherein defined shapes and sizes can be fabricated readily and reproducibly. Ideally such polymers must be biocompatible and bioabsorbable, nonimmunogenic, support cell growth, and be able to induce angiogenesis to supply the newly formed tissue. The most widely used polymers in tissue engineering fulfilling these criteria include the poly (alpha-hydroxy acids) of the aliphatic polyesters (polyglycolic acid (PGA), polylactic acid (PLA), and the copolymers (PLGA)) of these materials.
Bone marrow stromal cells (or mesenchymal stem cells) have been shown to have the potential of differentiating into cardiomyocytes in vitro after treatment with 5-azacytidine. Because these cells can be harvested repeatedly by bone marrow aspiration, can be expanded significantly in vitro, and do not require immunosuppression, they are an attractive cell source for cellular cardiomyoplasty. Fuchs J. R. et al. (2001). “Tissue engineering: a 21st century solution to surgical reconstruction.” Ann. Thorac. Surg. 72(2): 577-91.
The second approach to myocardial tissue engineering involves seeding cells onto a biodegradable scaffold. Tissue-engineered constructs have a definitive structure and may be more apt to produce a significant myocardial augmentation when transplanted as opposed to a cell suspension alone. Furthermore, biodegradable polymers such as PGA and poly-L-lactic acid are well suited for the delivery of a large number of cells because of their high porosity and surface area, which also allows for the vascularization and structural integration of the new tissue with surrounding native tissue after implantation. Fuchs, J. R. et al., 2001.
Clearly, there is a clinical need for a mini-invasive, safe and effective approach to treatment of pericardial effusion and tamponade. The present application takes advantage of a safe and effective pericardial access approach previously disclosed in combination with a special catheter used specifically for fluid drainage, fluid diagnosis, resuscitation and therapy delivery to treat the underlying cause of the effusion.
Thus, there is need for an efficient, easy to use, and relatively inexpensive device, system and technique that can be used to access the heart for local delivery of therapeutic and diagnostic substances, as well as of CRT leads and other types of leads. There is also a need for an efficient, easy to use, and relatively inexpensive device, system and technique that can be used to access a space containing fluid within a tissue to remove the fluid and to optionally deliver a substance if necessary. There is also a need for an efficient, easy to use, and relatively inexpensive device, system and method that can be used to effectively heal a myocardial infarct and reinforce its border zone.